Throughout this application various publications are referenced and citations provided for them. The disclosure of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Putrescine, also known as 1,4-butanediamine, is a normal nontoxic constituent of mammalian cells. Putrescine is formed via the decarboxylation of ornithine. The rate limiting enzyme in the synthesis of putrescine and other polyamines is ornithine decarboxylase. In rat prostate cells, ornithine decarboxylase activity is quite sensitive to in vivo inhibition by the polyamine depleting agent, difluoromethylornithine. In vitro inhibition by the polyamine depleting agent, difluoromethylornithine shows that depletion of polyamines caused by the addition of difluoromethylornithine enhances the uptake of exogenously added polyamines. Pretreatment with difluoromethylornithine in vivo significantly increases the uptake of radioactive putrescine by prostate cancer cells. Kadmon, et al., J. Nucl. Med., 23: 998-1002, No. 11 (November 1982).
Following treatment with the polyamine-depleting agent, difluoromethylornithine, putrescine and cadaverine, another polyamine, are taken up by prostate derived tumors much more readily than other polyamines. Heston, et al., Cancer Res. 44: 1034-1040 (1984).
The invention described herein relates to the use of putrescine-derived cytotoxic polyamines compounds as proliferation inhibitors of human prostatic cancer cells.
The invention described herein further relates to the use of polyamine-depleting agents to facilitate the uptake of cytotoxic polyamine compounds by human prostatic cancer cells.